EXCEED THE SPACE PROVIDED. Learning and memory disorders resulting from normal and pathological aging, brain trauma, developmental disorders, substance abuse, and traumatic experiencessuch as sexual abuse or combat, represent a major public health concern. The development of an understanding of brain mechanisms of memory and of animal models for use in applied studies, is critical to the ultimate development of effective theraputic interventions for these disorders. The encoding, storage, retrieval and consolidation of memory involves temporally extended interactions of large neural populations distributed widely over the brain. We propose the neurophysiological analysis of memory-related neural ensemble interactions within a linked system of brain regions that are important in mnemonic processes, including hippocampus and adjacent neocortical association areas, limbic cortex, ventral striatum and substantia nigra/ventral tegmentum. Our main focus is the process of spontaneous memory trace retrieval, defined as the spontaneous re-establishment of neural activity patterns that match those that were imposed by recent experience.This process can be studied by analyzing how statistical interactions among neural ensembles during the retrieval phase match those that were observed during encoding. Such off-line retrieval appears to play a critical role in the process of memory consolidation. We have established several important basic characteristics of this process: it occurs coherently among hippocampal and neocortical regions; it recreates,in a compressed form, the short-term temporal order of encodedexperiences;it is strongest during a period of 30-60 minutes after an experience, but can be observed at least 24 hours later. Of particular importance is our observation that hippocampal memory trace reactivation is expressedprimarily during a specific neurophysiological event, the hippocampal 'sharp-wave' (SPW). SPWs have been proposed on theoretical grounds to reflectthe convergence of hippocampal associative networks onto stored memory states, and our findings identify SPWs as memory readout events in the hippocampus. Much remains to be learned about the dynamics of these events within the hippocampus and how SPWtransmitted information interacts with neocortical dynamics to establish hippocampus- independent long-term memories in neocortical and other brain circuits. The proposed studies will both advance our understanding of the biology of memory and lead to the development of precise, quantitative animal models for use in drug developmentand other theraputic investigations. In particular, several of the proposed studies are of direct relevanceto understanding phenomena such as 'flashback' memory in post-traumatic stress disorder.